Quinolone- and naphthyridonecarboxylic acids and esters thereof are intermediates for preparing known, pharmaceutically active quinolone-carboxylic acids and naphthyridonecarboxylic acids, respectively.
EP-A-300,311 (Canadian Patent 1333715) discloses a preparation of quinolone-carboxylic acids where a benzoyl chloride is acylated with an aminoacrylic ester, and an amine exchange is carried out with the aroylacrylic ester. The resulting aminoacrylate is cyclized, the resulting ester is hydrolyzed, and the resulting quinolone-carboxylic acid is precipitated out by addition of an acid. The patent reports that yields between 71 and 79% are obtained. The solvents which are given for the for the acylation step include toluene, xylene, cyclohexane, open-chain hydrocarbons, and polar solvents such as dimethyl formamide (DMF) and dimethyl sulphoxide (DMSO). The solvents which are given for the amine-exchange step include the above-mentioned solvents as well as protic polar solvents, e.g., alcohols such as butyl glycol. Suitable solvents for the cyclization steps include only polar solvents such as higher alcohols, amino alcohols, DMF, DMSO, dioxane and N-methylpyrrolidone.
If non-polar to slightly polar solvents such as hydrocarbons are to be employed for the acylation and the amine exchange, a different polar, optionally even protic solvent, such as butyl alcohol, has to be employed for the cyclization. As such, to carry out the entire reaction in one solvent seems possible only in a strongly polar solvent such as DMF and DMSO. In the examples of EP-A 300 311, for instance, the solvent was changed, namely from the non-polar aprotic toluene or cyclohexane for the first solvent and, if appropriate, the second step to the polar, protic butyl glycol for the third and, if appropriate, second step.
The change of solvent leads to considerable expense for the separate removal of two different solvents, for drying the intermediate at whose stage the solvent exchange is carried out and for disposal or regeneration of two different solvents. Further, the yields which can be obtained are still not entirely satisfactory.
According to EP-A 176,846, for reacting a benzoyl halide with an acrylic acid derivative (=acylation), use is made of methylene chloride, chloroform, toluene, tetrahydrofuran or dioxane.
In Liebigs Ann Chem. 1987, 29-37, a dipolar aprotic solvent, for example, DMF, DMSO or N-methylpyrrolidone, is specified for the cyclocondensation of 3-amino-2-benzoylacrylic esters to 4-quinolone-3-carboxylic esters (=cyclization).
Thus, there is a general bias in the art against using a non-polar to slightly polar solvent for the entire reaction sequence.